Recent trials of T-cell depleted haploidentical hematopoeitic cell transplantation (HCT) suggest that NK cell reactivity can lead o less GVHD, reduced risks of relapse and improved overall survival when NK cells are NOT inhabited by recipient KIR ligands. In a cohort of Unrelated Donor (URD) HCT recipients at the University of Minnesota, no survival advantage was seen, suggesting that differences in clinical settings or other components of the relevant immunotiology may account for these disparate clinical results. The main hypothesis to be tested in this Program is that NK cells are of biologic importance in URD transplantation and that killer immunoglobulin-like receptor (KIR) interactions with MHC class 1 ligands can alter the clinical outcomes. This Program includes a group of international experts in NK cell biology and bone marrow transplantation collaborating to investigate the relevance of NK alloreactivity in URD HCT, a setting where KIR repertoires differ in nearly all donor-recipient pairs. We will utilize the many thousands of blood and DNA samples available through the National Marrow Donor Program (NMDP) and their high quality long-term follow-up data available on transplant outcomes. Project 1 will focus on the physiologic role of KIR differences inherent between donors and recipients using increasingly higher resolution of KIR determinations from simple gene content to haplotype organization. Novel KIR allele polymorphisms will be identified from these studies and their clinical significance will be determined. However, in many patients, KIR are not expressed normally after transplant. Therefore, in Project 2, NK cell development, the acquisition of functional KIR and the mechanisms that determine KIR expression will be studied. The retrospective NMDP cohort studies will facilitate immediate bedside to bench studies for Projects 1 and 2. In Project 3, prospective trials will exploit NK cell reactivity clinically and facilitate prospective evaluation of KIR genotype and KIR development based upon the work of Projects 1 and 2. Additionally, higher resolution KIR genotyping and matching will be studied for their impact on the risks of clinical complications after HCT. The synergistic interaction between all projects will take basic NK biology from the bench to the bee side to improve outcomes of URD HCT by better donor selection, KIR repertoire manipulation or enhancement of NK cell development. In addition to Administration (A) and Biostatistics (B) Cores, the projects are supported by scientific cores, each integrating with all projects for KIR genotyping (Core C), K.IR haplotype sequencing (Core D) and a KIR sequence public database (Core E). Taken together, these highly focused and integrated studies vv 11 definitively assess the role of NK cells and their receptors in URD IICT and broaden the success of alternative donor transplant, the only potentially curative therapy for many patients with advanced cancer.